1. Field of the Invention
The invention relates to a membrane module for hemodiafiltration, comprising a cylinder-shaped housing with a longitudinal extent housing a bundle of hollow-fiber membranes with semipermeable walls and capable of supporting fluid flow through their lumina arranged in the direction of the longitudinal extent of the housing. The ends of the hollow-fiber membranes are embedded in a fluid-tight manner in first and second sealing compounds joined to the housing inner wall in a fluid-tight manner such that an exterior space delimited by the first and second sealing compounds and the housing inner wall is formed around the hollow-fiber membranes. The exterior space along the longitudinal extent of the housing is divided into a dialyzate space and a substituate space by a dividing wall that is made from a substantially dimensionally stable material, encloses each hollow-fiber membrane, and is arranged substantially transversely to the hollow-fiber membranes, the dialyzate and substituate spaces each have at least one opening for introducing or withdrawing a fluid.
2. Discussion of Related Art
Hemodiafiltration is a combined membrane-based process for blood purification in which hemodialysis and hemofiltration are conducted concurrently. This process combines the advantages of convective substance transport in hemofiltration with those of diffusion in hemodialysis. In hemofiltration, blood is passed along the membrane of a hemofilter, a portion of the blood liquid being withdrawn through the membrane by ultrafiltration. This partial stream is replaced by a sterile and pyrogen-free substitution liquid, or substituate, that is delivered to the extracorporeal blood stream either upstream from the hemofilter in the form of predilution or downstream from the hemofilter in the form of post-dilution. In addition, in hemodiafiltration the usual hemodialysis is conducted as well, wherein a dialysis liquid or dialyzate is passed along the membrane of the hemodialyzer such that substances usually eliminated with the urine can be removed through the membrane.
The combination of diffusive substance transport with convective substance transport in hemodiafiltration permits the advantageous removal of more than only substances from the blood having a low molecular weight that are usually eliminated with the urine. Slowly diffusing medium molecules with molecular weights from about 1 to 55 kD profit especially from the convective substance transport, and that is all the more so as these molecules increase in size and as the filtrate stream through the membrane increases. Typically, at about 60 kD, the membranes are intended to be essentially impermeable, so that the patient does not pass more than 4 g of protein from the blood into the dialyzate during a 4-hour treatment.
In the conventional hemodialysis process, only the amount of liquid the patient has taken in between the dialysis treatments is removed from the blood via the dialysis membrane as ultrafiltrate. The amount of liquid removed in this process is about 6 to 8% of the blood volume stream. In conducting current hemodialysis processes, so-called volume-controlled dialysis machines are generally used. They monitor the net amount of liquid removed according to the preset net filtration by balancing the dialysis liquid stream fed to the dialyzer with the dialyzate stream withdrawn from the dialyzer,
In hemodiafiltration, on the other hand, the amount of ultrafiltrate is significantly higher, from about 20 to 30% of the blood volume stream, due to the liquid fraction needed to increase the convective transport through the membrane. In the end, the net amount of liquid withdrawn from the patient is the same as that in conventional hemodialysis. The amount of liquid exceeding that needed to increase the convective transport is, as noted, replaced by a substituate.
To conduct hemodiafiltration processes, modified dialysis machines are generally used that permit monitoring of the ultrafiltration rates and balance the ultrafiltration and substituate volume streams.
Different requirements are usually imposed with respect to the purity of the dialysis and substitution liquids. The dialysis liquid can be prepared online from fresh water and an electrolyte concentrate, where the fresh water is normally germ-free and the electrolyte concentrate is inherently sterile. The substitution liquid itself can be prepared online from the dialysis liquid, but it is not generally required that the dialysis liquid prepared online is absolutely sterile and free of endotoxins, pyrogens and CIS.
Endotoxins are cell remnants of dead bacteria. The endotoxin concentration is usually determined using the so-called LAL test, a biological assay such as that manufactured by BioWhittaker, Inc., for example. Pyrogens are temperature-elevating substances. When infused in rabbits, for example, they cause an increase in body temperature. Pyrogens can include endotoxins and exotoxins. The latter are produced by living bacteria. In human blood, these substances lead to stimulation of monocytes that themselves produce cytokines and thus trigger a cascade of additional cell stimulations. Today, endotoxins, exotoxins, pyrogens, and other substances from the dialyzate that stimulate the blood are grouped under the abbreviation CIS (cytokine inducing substances). One of the relevant cytokines produced by stimulation of stimulated monocytes is interleukin 6 (IL 6). The determination of CIS by detection of IL 6 is described in B. L. Jaber et al., Blood Purif. 1998, Vol. 16, pp. 210-219, for example.
For this reason, the dialysis liquid for preparing the substitution liquid should be converted to the sterile and ideally CIS-free state, using a filter, for example. Of course, the substitution liquid prepared in this manner can also be used as a dialysis liquid. Modem dialysis machines generally include a facility with which the dialyzate is filtered online such that it has an endotoxin concentration of less than 0.5 EU per ml of dialyzate. As a result, patients experience almost no pyrogen reactions, even in the case of so-called high-flux dialysis, which are frequently observed with dialyzate contaminated with endotoxins. However, with an endotoxin concentration of <0.03 EU/ml, which is the detection limit of the conventional LAL tests, CIS might still be present in the dialyzate. The requirement for CIS-free dialyzate is therefore more stringent than that for LAL-negative dialyzate.
In EP-A 692 269, a hemodiafiltration apparatus is described with two blood filters connected in series. The blood filters each contain membranes, one side of which is subjected to a flow of blood to be purified and the other side to a dialysis liquid flow. The dialysis is passed through a sterile filter prior to being fed to the hemodiafiltration apparatus. In the apparatus described in EP-A 692 269, a transfer of dialysis liquid as a substitution liquid directly into the blood takes place in one of the two blood filters in the direction of the blood flow due to the positive transmembrane pressure set at this point via the membrane of this blood filter. A negative transmembrane pressure is generated in the second blood filter, where separation of a portion of the blood liquid and removal of substances normally eliminated in the urine into the dialyzate take place via diafiltration.
Such hemodiafiltration apparatus with blood filters connected in series are complex in operation and can generally not be used in commercially available dialysis machines due to the design and the special and complex controls associated with it.
EP-A 451 429 also discloses a hemodiafiltration apparatus having two membrane modules connected in series. In this case, the first membrane module is a hemofilter in which a partial stream of liquid is withdrawn by ultrafiltration from the blood to be purified, wherein the partial stream primarily contains the medium-molecular substances to be removed from the blood. The ultrafiltrate is regenerated in a special filter and reintroduced to the blood stream before the latter is directed into the second membrane module. This blood stream is then subjected to hemodialysis in the second membrane module.
In addition to the previously cited disadvantages of separate blood filters connected in series, the hemodiafiltration apparatus described in EP-A 451 429 has the drawback that it requires a special regenerator that must be used to purify the ultrafiltrate.
In DE-A 196 07 162, a hemodiafiltration system is described with controlled delivery of a substituate and a dialyzate into a dialyzer, wherein the dialyzer is designed as a single component for blood treatment, substituate filtering, and mixing of the substituate with the blood to be treated. The dialyzer contains two adjacent membrane modules in its longitudinally extended housing, each with a bundle of hollow-fiber membranes. The membrane modules are separated from each other by a dividing wall substantially parallel to the hollow-fiber membranes. The first membrane module is used for hemodiafiltration and the second membrane module for sterile filtration of the substituate. The dialyzer further comprises a chamber in which purified substituate is reunited with the blood to be treated.
While the hemodiafiltration system described in DE-A 196 07 162 has a simpler and clearer construction compared to the systems with multiple blood filters connected in series, the manufacture of the two-module dialyzers disclosed in DE-A 196 07 162 is difficult, particularly due in part to the handling of two different hollow-fiber membrane bundles. Furthermore, the membrane modules in the dialyzer are not arranged rotationally symmetrically, so that there is a risk of non-uniform flow, in particular through the external space surrounding the hollow-fiber membranes of the first membrane module, which is used for hemodiafiltration. Furthermore, the dialyzers as described in DE-A 196 07 162 also require an additional pump device for the substituate transport, which is not present in conventional dialysis machines today.
EP-A 701 826 discloses a hemodiafilter that has a single bundle of hollow-fiber membranes for blood treatment, filtration of the substituate, and delivery of the substituate to the blood. In this hemodiafilter, a material is present in the external space of the hemodiafilter surrounding the hollow-fiber membranes that undergoes dimensional changes, i.e., swells, through the dialysis liquid when this hemodiafilter is used for hemodiafiltration, leading to a restriction. This generates a pressure drop between the upstream and downstream sides of the restriction for the dialysis liquid flowing through the external space. Materials that can swell due to the dialysis liquid include, for example, various copolymers that are applied at the desired location on the hollow-fiber membranes, or fiber-shaped materials, capable of swelling, that are woven with the hollow-fiber membranes.
The insertion of the swellable material is complex, on one hand. On the other hand, a precise, stable, and reproducible positioning across the bundle cross-section is not guaranteed and cannot be achieved in practice. There are also narrow limits imposed on the materials capable of swelling that can be used since the use of the hemodiafilter for blood purification requires a high degree of hemocompatibility for the materials used, due to the contact with body liquids. Since, according to EP-A 701 826, the degree of swelling of the inserted swellable material depends on the dialysis liquid used, the degree of swelling is difficult to control and reproduce. The effect of the restriction caused by this material on the dialyzate and substituate flow cannot be determined in advance, or it requires at least comprehensive preliminary tests and complex estimations. Furthermore, due to the swelling there is a dependence of the material dimensions and thus the cross-section restriction on the differential pressure applied, and in an unfavorable case an increase in the pressure differential can lead to complete blockage.
From the previously described disadvantages, it can readily be concluded that controllable and reproducible flow conditions are not present when the hemodiafilters disclosed in EP-A 701 826 are used.